PROJECT 1: Systems Analyses of Heterologous Immunity During CMV Infection in Renal Transplantation SUMMARY/ABSTRACT The main complications of solid organ transplantations are rejection and opportunistic latent herpes virus infections, the predominant player being cytomegalovirus (CMV). Primary infections, as well as latency, normally occur asymptomatically in immunocompetent hosts. In immunocompromised patients, coexistence of CMV with the host is a precarious balance that can result in viral reactivation, a phenomenon associated with high morbidity and mortality. The overarching goal of the project is to define the effects of CMV infection on innate and adaptive immune responses in transplant recipients and to disseminate our findings to the broader scientific community. Our central hypothesis is that identifying the continuum of innate and adaptive immune phenotypes before, during and after CMV infection will provide mechanistic insights into CMV pathogenesis and novel tools to select, monitor and refine clinical practice, thereby improving patient outcomes. We also postulate that exposure to CMV upon primary infection or reactivation in immunocompromised transplant recipients induces crossreactivity to donor antigens, thus increasing the risk of allograft rejection. Improved understanding of the relationship between CMV and alloimmunity will provide practical tools for clinical immune assessment and improved therapies. We plan to reach these goals through the following Aims: Aim 1. Construct an in-depth longitudinal immune profile of renal transplant recipients during CMV infection. We hypothesize that CMV infection/reactivation is associated with a common immune profile providing a mechanistic framework to identify biomarkers for risk assessment and guiding therapy. Aim 2. Define the role of CMV infection on the generation of heterologous T cell alloimmunity. We hypothesize that TCR cross-reactivity of T cells specific for CMV and alloantigen will promote heterologous immunity, leading to increased alloimmunity and potentiation of antiviral responses.